cytosporone-b and Disease-Models--Animal

Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of

Topics: Adult; Aged; Aged, 80 and over; Animals; Breast; Breast Neoplasms; Cell Proliferation; Disease Models, Animal; Disease Progression; DNA-Binding Proteins; Fatty Acids; Female; Humans; Kaplan-Meier Estimate; Lipid Metabolism; Mammary Glands, Animal; Mice; Middle Aged; Nuclear Receptor Subfamily 4, Group A, Member 1; Phenylacetates; PPAR gamma; Primary Cell Culture; Prognosis; Proteolysis; Tissue Array Analysis; Tumor Cells, Cultured; Tumor Suppressor Proteins; Ubiquitination

Excess fibrosis may lead to chronic pain, scarring, and infertility as endometriosis develops and progresses. The pathogenesis of endometriosis has been linked to transforming growth factor-β (TGF-β), the most potent promoter of fibrosis.. Levels of NR4A1 and P-NR4A1 protein in human endometrial and endometriotic tissue were assessed by western blotting and immunohistochemistry. The expression levels of fibrotic markers in stromal cells were evaluated by real-time PCR. The degree of fibrosis in mouse endometriotic lesions was detected by Masson trichrome and Sirius red staining.. The level of phosphorylated-NR4A1 was higher in ovarian endometriotic tissue than in normal endometrium, and long-term TGF-β1 stimulation phosphorylated NR4A1 in an AKT-dependent manner and then promoted the expression of fibrotic markers. Furthermore, inhibition of NR4A1 in stromal cells increased the TGF-β1-dependent elevated expression of fibrotic markers, and loss of NR4A1 stimulated fibrogenesis in mice with endometriosis. Additionally, Cytosporone B (Csn-B), an NR4A1 agonist, effectively decreased the TGF-β1-dependent elevated expression of fibrotic markers in vitro and significantly inhibited fibrogenesis in vivo.. NR4A1 can regulate fibrosis in endometriosis and may serve as a new target for the treatment of endometriosis.

Topics: Adult; Animals; Cells, Cultured; Collagen Type I; Collagen Type I, alpha 1 Chain; Connective Tissue Growth Factor; Disease Models, Animal; Endometriosis; Endometrium; Female; Fibronectins; Fibrosis; Heterocyclic Compounds, 3-Ring; Humans; Mice; Mice, Nude; Microscopy, Fluorescence; Nuclear Receptor Subfamily 4, Group A, Member 1; Phenylacetates; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA Interference; RNA, Small Interfering; Stromal Cells; Transforming Growth Factor beta; Transplantation, Heterologous; Up-Regulation; Young Adult

Monocytes are central to the physiopathology of arthritis, but their roles in progression and resolution of the disease remain to be clarified. Using NR4A1

Topics: Animals; Anti-Inflammatory Agents; Antigens, Ly; Arthritis; Cells, Cultured; Disease Models, Animal; Female; Humans; Inflammation; Joints; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Nuclear Receptor Subfamily 4, Group A, Member 1; Phenylacetates; T-Lymphocytes, Regulatory

Acute respiratory distress syndrome (ARDS) is characterized by inflammatory injury to the alveolar and capillary barriers that results in impaired gas exchange and severe acute respiratory failure. Nuclear orphan receptor Nur77 has emerged as a regulator of gene expression in inflammation, and its role in the pathogenesis of ARDS is not clear. The objective of this study is to investigate the potential role of Nur77 and its underlying mechanism in the regulation of endothelin-1 (ET-1) expression in lipopolysaccharide (LPS)-induced A549 cells and an ARDS rat model. We demonstrate that LPS induced Nur77 expression and nuclear export in A549 cells. Overexpression of Nur77 markedly decreased basal and LPS-induced ET-1 expression in A549 cells, whereas knockdown of Nur77 increased the ET-1 expression. LPS-induced phosphorylation and nuclear translocation of NF-κB and p38 MAPK were blocked by Nur77 overexpression and augmented by Nur77 knockdown in A549 cells. In vivo, LPS induced Nur77 expression in lung in ARDS rats. Pharmacological activation of Nur77 by cytosporone B (CsnB) inhibited ET-1 expression in ARDS rats, decreased LPS-induced phosphorylation of NF-κB and p38 MAPK, and relieved lung, liver, and kidney injury. Pharmacological deactivation of Nur77 by 1,1-bis-(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH, C-DIM8) had no effect on ET-1 expression and lung injury. These results indicated that Nur77 decreases ET-1 expression by suppressing NF-κB and p38 MAPK in LPS-stimulated A549 cells in vitro, and, in an LPS-induced ARDS rat model, CsnB reduced ET-1 expression and lung injury in ARDS rats.

Topics: A549 Cells; Active Transport, Cell Nucleus; Animals; Cell Nucleus; Disease Models, Animal; Down-Regulation; Endothelin-1; Kidney; Lipopolysaccharides; Liver; Lung; Male; NF-kappa B; Nuclear Receptor Subfamily 4, Group A, Member 1; p38 Mitogen-Activated Protein Kinases; Phenylacetates; Rats, Sprague-Dawley; Respiratory Distress Syndrome; RNA, Messenger